A fragment-based approach identifies an allosteric pocket that impacts malate dehydrogenase activity

Malate dehydrogenases (MDHs) sustain tumor growth and carbon metabolism by pathogens including Plasmodium falciparum. However, clinical success of MDH inhibitors is absent, as current small molecule approaches targeting the active site are unselective. The presence of an allosteric binding site at oligomeric interface allows the development of more specific inhibitors. To this end we performed a differential NMR-based screening of 1500 fragments to identify fragments that bind at the oligomeric interface. Subsequent biophysical and biochemical experiments of an identified fragment indicate an allosteric mechanism of 4-(3,4-difluorophenyl) thiazol-2-amine (4DT) inhibition by impacting the formation of the active site loop, located >30 Å from the 4DT binding site. Further characterization of the more tractable homolog 4-phenylthiazol-2-amine (4PA) and 16 other derivatives are also reported. These data pave the way for downstream development of more selective molecules by utilizing the oligomeric interfaces showing higher species sequence divergence than the MDH active site.

Downstream Suppression of Baroclinic Waves

Baroclinic waves drive both regional variations in weather and large-scale variability in the extratropical general circulation. They generally do not exist in isolation, but rather often form into coherent wave packets that propagate to the east via a mechanism called downstream development. Downstream development has been widely documented and explored. Here we document a novel but also key aspect of baroclinic waves: the downstream suppression of baroclinic activity that occurs in the wake of eastward propagating disturbances. Downstream suppression is apparent not only in the Southern Hemisphere storm track as shown in previous work, but also in the North Pacific and North Atlantic storm tracks. It plays an essential role in driving subseasonal periodicity in extratropical eddy activity in both hemispheres, and gives rise to the observed quiescence of the North Atlantic storm track 1–2 weeks following pronounced eddy activity in the North Pacific sector. It is argued that downstream suppression results from the anomalously low baroclinicity that arises as eastward propagating wave packets convert potential to kinetic energy. In contrast to baroclinic wave packets, which propagate to the east at roughly the group velocity in the upper troposphere, the suppression of baroclinic activity propagates eastward at a slower rate that is comparable to that of the lower to midtropospheric flow. The results have implications for understanding subseasonal variability in the extratropical troposphere of both hemispheres.

Downstream development strategy of processing industry in Jambi Province

The food and beverage industry, the paper and paper goods industry, and the rubber industry, rubber and plastic goods are leading industries that play an important role in the regional economy of Jambi Province. Therefore, policies are needed to sustain leading industries' growth and development. This research aims to formulate a downstream strategy for the leading processing industry in Jambi province. The method used is the Analytical Network Process (ANP). The analysis results show that the priority strategy in the downstream development of the three leading industries in Jambi Province is optimizing the government's role in policy and funding for the downstream program.

The Effect of Quadric Shear Zonal Flows and Beta on the Downstream Development of Unstable Baroclinic Waves

In this paper, the influence of quadric shear basic Zonal flows and β on the downstream development of unstable chaotic baroclinic waves is studied from the two-layer model in wide channel controlled by quasi geostrophic potential vorticity equation. Through the obtained Lorentz equation, we focused on the influence of the quadric shear zonal flow (the second derivative of the basic zonal flow is constant) on the downstream development of baroclinic waves. In the absence of zonal shear flow, chaotic behavior along feature points would occur, and the amplitude would change rapidly from one feature to another, that is, it would change very quickly in space. When zonal shear flow is introduced, it will smooth the solution of the equation and reduce the instability, and with the increase of zonal shear flow, the instability in space will increase gradually. So the quadric shear zonal flow has great influence on the stability in space.

Three Lessons on the Construction of Export Controls Under WTO Law

Export controls are gradually emerging as a source of contention within the World Trade Organisation (‘WTO’) law. Resource-exporting developing countries are increasingly finding it difficult to reserve the use of commodities and mineral resources for domestic purposes and downstream development due to the obligations imposed by the General Agreement on Tariffs and Trade (‘GATT’) framework and WTO law. The problem is further exacerbated by the unclear guidelines and the overwhelming import-orientation of the provisions regulating international trade within the GATT/WTO framework. This article synthesises three important lessons that can be gleaned by policymakers from GATT/WTO jurisprudence in the construction of export controls in order to avoid a hostile response from other WTO Members concerned about equitable and free access to resources. The article argues that, as things stand today, GATT provisions leave little room for policymakers to prefer budding domestic sectors. Any preferential policies that seek inward diversion of resources will most likely attract a challenge in the WTO Dispute Settlement Body.

The Effect of Beta on the Downstream Development of Unstable, Chaotic Baroclinic Waves

The weakly unstable, two-layer model of baroclinic instability is studied in a configuration in which the flow is perturbed at the inflow section of a channel by a slow and periodic perturbation. In a parameter regime where the governing equation would be the Lorenz equations for chaos if the development occurs only in time, the solution behavior becomes considerably more complex as a function of time and downstream coordinate. In the absence of the beta effect it has earlier been shown that the chaotic behavior along characteristics renders the solution nearly discontinuous in the slow downstream coordinate of the asymptotic model. The additional presence of the beta effect, although expunging the chaos for large enough values of the beta parameter, also provides an additional mechanism for abrupt spatial change.